Some individuals treated during acute HIV-1 infection with antiretroviral therapy now appear to be able to immunologically suppress HIV-1 replication for at least six months following discontinuation of therapy. Similar scenarios have not yet been well documented for people treated at a later stage of the infection, though HIV-specific CD8+ and CD4+ T cell responses are sometimes detectable. The desired effect of an immune response to HIV-1 is complicated by the fact that CD4+ T cells themselves are infected and may be further depleted by the immune response. Although CD4+ counts often recover after antiretroviral therapy, this recovery is largely due to redistribution and expansion of remaining memory cell clones. De novo T cell development, required for the generation of a widely diverse T cell repertoire, requires the thymus, which typically involutes after puberty. However, we have evidence showing that rebound of thymic mass and increased de novo T cell production can occur in some HIV-1-infected adults. The hypothesis of this application is that chronically HIV-1-infected individuals who have suppressed viral replication on HAART and who have increased thymic output compared to age-matched seronegative controls will generate and maintain HIV-1-specific immune responses that can control viremia during controlled interruptions of antiretroviral therapy. To test this hypothesis the following specific aims are proposed: 1) to prospectively assess the degree of thymic output in chronically infected people undergoing scheduled interruptions of antiretroviral therapy and to stratify these patients into two groups having either high or low thymic output compared to age-matched seronegative controls; 2) to phenotypically and functionally characterize HIV-1-specific T cell responses during scheduled treatment interruptions (STI) in the two subject groups stratified by thymic output; and 3) to measure the ability of HIV-1-specific T cell responses generated during STI in the two subject groups stratified by thymic output, to control the replication of autologous virus, as demonstrated not only in vivo by the pattern of rebound viremia, but also in vitro, by indirect and direct methods. The award candidate is a pediatric immunologist at the University of California, San Francisco, doing postdoctoral research on human thymic function in J.M. McCune's laboratory at the Gladstone Institutes. He intends to become an independent academic investigator and to continue to conduct patient-oriented research in the area of immunodeficiency disorders.